The above statement of Paul Gelsinger, who withdrew
his teenage son Jesse from life support after an infusion of
gene-altered viruses meant to correct an enzyme deficiency
triggered an immune reaction that went awry, expresses a parent's
distress at being inadequately advised about a University of
Pennsylvania gene therapy experiment in which he encouraged his
child to participate. Neither father nor son recognized that the
experiment bestowed no benefit upon the teenager and had been
fashioned to evaluate the safety of a treatment for babies with a
fatal form of Jesse's disorder. Mr. Gelsinger, who now regards his
decision to trust Penn researchers as naïve, was unaware both
of the risks involved in the study and that despite three hundred
clinical trials, gene therapy had never cured anyone.[2] Researchers instead procured Jesse's participation
by implying that therapy received might combat his disease.

This case proves particularly troubling because of
a flagrant disregard for the process of informed consent: federal
regulations mandate that potential risks and benefits be outlined
to patients in lay language and that if some participants in a
study experience grave side effects, all volunteers must be
apprised of developments and consent again. The informed consent
form the Gelsingers reviewed, however, excluded mention of monkeys'
death subsequent to administration of a similar treatment, and when
patients suffered changes in liver enzyme levels dire enough to
terminate the trial, the consent form remained unrevised. FDA
investigations further reveal that researchers enrolled all
eighteen patients without completing eligibility forms and poorly
documented the consent process for half of these subjects. Such
flaws in informed consent are routine; the director of the Office
for Protection from Research Risks reports that over 90 percent of
cases of alleged abuse he investigates uncover lapses in informed
consent.[3]

Exacerbating the distress this case evokes is the
fact that the teenager was not seriously ill before his death. His
mild liver disorder was controlled adequately through diet and
medication. The incident thus highlights the manner in which
optimism divaricates in clinical trials when researchers hope to
discover if novel treatments prove hazardous, yet subjects expect a
cure. Although the population at large generally looks favorably
upon biomedical research, this botched gene therapy study provokes
questions concerning the nature of medical progress, the procedures
by which cutting-edge technology is and should be developed,
executed, and evaluated, as well as what constitutes proof of
therapeutic efficacy and who should render efficacy
determinations.[4] Researchers' quests for general progress or a cure
now clearly endanger basic values such as human dignity and
autonomy, leading Senator Bill Frist to comment after Congressional
hearings on the Gelsinger tragedy that we must confront a
"multisystem failure" of safeguards currently in place if we are to
protect patients.[5]

Pharmaceutical companies, researchers, advocacy
organizations, and politicians have criticized human
experimentation regulation, currently achieved through a "crazy
quilt of hortatory codes and maxims, scattered federal laws and
regulations and...Institutional Review Boards" (hereafter
IRBs).[6] IRBs and regulations do not sufficiently entrench
the rights of patient-subjects. While IRBs must exercise heightened
vigilance to safeguard vulnerable populations such as prisoners,
children, pregnant women, and the mentally disabled[7] - i.e. those particularly susceptible to
exploitation and duress due to factors such as diminished
decision-making abilities or "captivity" of institutionalization-
federal regulations utterly fail to provide adequate protections
for numerous groups, including the terminally ill, children, and
the mentally disabled. Guidelines additionally have worked
systematically to disadvantage other groups, most notably women.
Traditional exclusion of females from research under protectionist
auspices has led to the marketing of medical products posing danger
to women and has deprived seriously ill women of access to
experimental treatment offering their only hope of survival.

Modern medical breakthroughs compound the
shortcomings of the regulations, for the advent of AIDS and HIV
treatments as well as experimental cancer therapies have rendered
access to trials, rather than exclusion, the objective of
vulnerable populations. Patients demanding easier access to new
therapies willingly volunteer for unproven treatments. This creates
difficulty in that patients cannot make informed choices to try
potentially dangerous new technologies due to numerous unknowns
involved[8] and underscores the bifurcation of patients'
autonomy and their best interests. As human experimentation has
come to be regarded as beneficial rather than suspect, the
traditional line between research/experimentation and clinical
practice/therapy has blurred and monetary issues have subordinated
concerns for the rights and well-being of patient-subjects.
Informed consent, aimed at promoting autonomy and protecting the
individual subject, crumbles when research participation is offered
in a clinical setting. Forthright discussion and deliberation
requisite for meaningful consent is unlikely when patients suffer
from a therapeutic misconception and when competing interests,
namely those of the scientific community and those of society,
exist. The medical community thus must embrace the need to subject
certain research trials to greater scrutiny, and informed consent
must be revamped. A few monolithic standards and regulations
guiding procurement of consent are insufficient. Researchers must
consider the unique needs and vulnerabilities of different groups
and adjust the consent process to respond better to modern research
such as gene therapy.

To demonstrate the inadequacies of informed consent
in the contemporary context and the need for better subject
protection, this paper begins by scrutinizing the rise of modern
informed consent doctrine in international legal documents as well
as in the United States arena. After examining the federal
regulatory framework governing experimentation with human subjects,
considerable attention is given to the doctrine of informed consent
and its shortcomings in the research setting, including lack of
competence to grant consent, misunderstandings and conflicts of
interest between researcher and subject, and the doctrine's
incompatibility with several dynamics of the patient-physician
encounter. Flaws pertaining to both the research and therapeutic
settings are also noted. IRBs' responsibilities for protecting
subjects are then explored, along with the numerous factors
preventing these bodies from providing adequate safeguards. The
paper then discusses current regulations regarding various groups-
the terminally ill, women, children, prisoners, and the
decisionally/cognitively impaired, including psychiatric patients
and the elderly- as well as considerations unique to each. This
uncovers shortcomings of current informed consent doctrine and
illustrates that meaningful consent can only be achieved by
crafting procedures and policies specifically tailored to the needs
of each particular population. Next, problems that modern medical
research in the gene therapy area raises are probed, and numerous
proposals to ameliorate the informed consent process as well as IRB
efficacy are offered.

The Rise of Human Experimentation Regulation in
the International and National Arenas

Legal proceedings in 1947 against Nazi doctors who
subjected "volunteers" to epidemics such as malaria and typhus,
injection with poisons, sterilization, and to various other
atrocities led to the announcement of contemporary ethical
principles to govern international research standards, known as the
Nuremberg Code. The Code, consisting of ten principles of human
experimentation, flagged the dawn of heightened scrutiny of human
subject experimentation.[9] Its most frequently cited provision is the
first:

Placing this ideal in text proved significant in
the wake of the Second World War, during which the United States
committed egregious abuses of individual rights. While the notion
of consent had played a role in American research ethics and law
since the 1830's, it was not until the Code that consent principles
were formally reduced to writing.[11] Consent of the subject is necessary but not
sufficient under the Code, whose other guidelines pertain to the
welfare of subjects, must be met prior to the seeking of consent,
and cannot be waived.

While the Judges at Nuremberg intended universal
application of the document, which remains the most authoritative
script setting international research standards and one of the most
eminent human rights manifestos, it has fallen short of its aims.
The Code is often regarded as a response to Nazi terror and
trivialized as a context-bound relic no longer helpful in the
modern research milieu. Critics contend that the document proves
too demanding, fails to recognize the ideals of scientists, and
that its absolutism cannot operate in conjunction with the
impersonal and utilitarian ethics of contemporary
medicine.[12] Furthermore, uncertainty arises from the Code's
opening line stating that voluntary consent of the subject is
essential by seemingly precluding experimentation with emergency
patients, children, and the decisionally impaired.

Due to such shortcomings, the World Medical
Association has endeavored to unfrock the Code with the Declaration
of Helsinki, promulgated in 1964 and subsequently revised three
times. The Declaration consists of recommendations by physicians to
their peers and aims to displace the human rights-based goals of
the Code with a more indulgent medical ethics agenda tolerating
paternalism. Amendments to the document dropped references to
"informed" consent and added that physicians need not secure a
subject's consent to medical research combined with professional
care if they submit a reason for not obtaining consent to an
independent review committee. The Declaration is most notable,
however, for beginning to blur the line between treatment and
research by bifurcating research into "therapeutic" and
"nontherapeutic," a distinction referring to whether or not it may
prove directly beneficial to the subject. With respect to research
on terminal illnesses such as AIDS, this distinction means that
research will be deemed therapy. A drawback of the Declaration as
well as the Code it sought to supplant is that both are merely
hortatory; neither possess legal status in most countries nor
furnish sanctions or enforcement mechanisms. Both have been
condemned as extremely ambiguous, "representing nothing more than
'pious hopes' that doctors will behave ethically."[13]

In this country, disregard for groups such as
prisoners, the elderly, and the mentally disabled in no way
subsided in the wake of the Nuremberg Code and Declaration of
Helsinki. Scrutiny of contemporary human experimentation in the
United States reveals that enforceable domestic regulation was
necessary to curb abuses. The government endorsed regular testing
of vaccines for the military on the mentally disabled without their
consent during the Second World War, offering feckless utilitarian
justifications for experiments contravening human dignity. In
1952-3, an inmate of the New York Psychiatric Institute also died
at the hands of the government, a casualty of the institution's
secret contract with the Army Chemical Corps to conduct research
employing a mescaline derivative. The Atomic Energy Commission
simultaneously financed studies to demonstrate non-belligerent uses
of nuclear energy. In one experiment, investigators used
emotionally disturbed adolescent boys in Massachusetts institutions
to examine mineral intake in the human body by employing minute
amounts of radiation in breakfast cereal as a tracer. At one such
institution, researchers asked parents to consent to their child's
participation in a special program entitled the "science club"
without being told its true purpose, that ingestion of radiation
would occur, and that the research offered no prospect of medical
benefit.[14] Another flagrant research abuse that extended no
direct benefit to subjects nor contributed to knowledge of their
impairment occurred in 1963 with decisionally impaired patients at
the Brooklyn Jewish Chronic Disease Hospital, where debilitated
residents received live cancer cell injections without their
knowledge. Investigators seeking to gain an understanding of the
manner in which patients with non-cancerous chronic conditions
respond to the presence of transplanted cells argued that failure
to seek consent had occurred in more dangerous procedures and that
they feared frightening patients. Other contemporary ethically
questionable experiments involved a contraceptive study using
impoverished Mexican-American women who were assured they would
receive birth control when half received placebos and a hepatitis
study using inmates of an institution for developmentally disabled
children.

In 1966, Henry Beecher authored a landmark article
in the New England Journal of Medicine drawing attention to
a formidable list of unprincipled research being conducted at the
nation's most elite universities. Discovery of events such as the
Tuskegee studies of 1932-72, in which researchers seeking to
ascertain the death rates for untreated cases of syphilis recruited
infected black men by promising free treatment but actually charted
the progress of their disease and let them die,[15] also produced considerable controversy. The two
events spurred development of federal regulations now governing the
conduct of human research.

Senate hearings on human experimentation and the
passage of the National Research Act of 1974 made the mid-1970's
the dawn of a more comprehensive federal policy on research ethics.
This legislation established the National Commission for the
Protection of Human Subjects of Biomedical and Behavioral Research,
which identified basal ethical precepts that would underlie human
research and suggested guidelines for studies that the then
Department of Health, Education, and Welfare supported. The fruit
of its efforts yielded the 1979 Belmont Report, which considers the
line to be drawn between the practice of biomedical therapy and
research and announces the principles of respect for persons,
beneficence, and justice as especially significant to
experimentation with human subjects. The Report explains that
respect for persons involves persons being treated as autonomous
agents and individuals with diminished autonomy being entitled to
protection. Beneficence mandates that the harm threatening subjects
in a particular study or in the entire enterprise of research be
minimized or mitigated through affirmative efforts to secure
patients' well-being.[16] To apply these principles, the Report requires
informed consent, risk/benefit assessment, and the appropriate
selection of subjects of research as well as equitable distribution
of benefits of research. For truly informed consent, the Report
mandates that subjects be furnished with enough information, such
as the research procedure, its purpose, potential risks and
benefits, the existence of alternative procedures, and statements
offering the opportunity to raise questions and to withdraw from
the study at any time, to choose an appropriate course.

The Report, does not, however, address what quantum
of information should be provided. Furthermore, much research may
be justified even when subjects are not the direct beneficiaries of
the research if participation in research may lead to both the
increase of knowledge as well as to the development of improved
procedures.[17] Finally, the National Research Act requires that
every body applying for a grant or contract implicating biomedical
or behavioral research using human subjects submit assurances
satisfactory to the Secretary of Health, Education, and Welfare
that it has established an IRB to review the project and to
safeguard subjects' rights. The Report thus announces a doctrine of
informed consent with similar requirements for therapy and
research, the only difference being that the process for the latter
involves IRB scrutiny. Because experimentation occurs in the realm
of the unknown and unproven, however, numerous features
differentiate it from treatment: risks may not be easily
identifiable, a subject's consent cannot be grounded on anticipated
benefits, researchers and subjects may have diverging interests,
and assumptions are unsubstantiated by scientific evidence.
Expertise in this realm is thus more vulnerable than in clinical
practice.[18]

The Belmont Report's legacy proves remarkable, for
the document's distinction between "research" and "therapy" has
shaped informed consent ever since its formulation. While federal
regulations guiding human subject research manifest theoretical
foundations in the Belmont Report, they struggle with scenarios
involving aspects of both research and therapy. Confusion thus
arises about how to categorize interventions defying strict
categorization and "increases when [research] is conducted on sick
subjects because such research routinely takes place in a clinical
setting, where the atmosphere is more conducive to a focus on the
patient's trust of the physician and sometimes less attentive to
the subject's right to a full disclosure of information."[19]

As federal funding for scientific research
increased in the decade prior to the Belmont Report, FDA and
Department of Health and Human Services (hereafter DHHS) also
heightened their regulatory involvement in human research,
translating experimentation into a tightly controlled enterprise.
As the regulations currently stand, the 1991 common Federal Policy
for the Protection of Human Subjects[20] governs activities which any of seventeen
federal departments and agencies sponsor. Known as the "Common
Rule," the Policy codifies 1981 enactments of DHHS regulations
which honor the principle of autonomy in informed consent. DHHS
supervises protection of human research subjects utilizing review
at the federal and institutional levels, and to receive research
funds, institutions must guarantee in writing that investigators
will heed ethical principles of the Belmont Report and requirements
of §45 C.F.R. 46. These regulations delineate general
protections for all human subjects and additionally permit IRBs to
implement supplemental safeguards for experiments involving
vulnerable populations.[21] They do not, however, reach privately funded
research. Regulations promulgated under the Food, Drug, and
Cosmetic Act govern such study aimed at introducing a new drug or
medical device to market. Additionally, all domestic clinical
trials involving investigational drugs are under FDA oversight,
regardless of funding source. The joint effect of DHHS and FDA
regulations proves significant, for federal policy thus controls
most human subject and drug research performed
domestically.[22]

Because society now views exclusion from research
as "discriminatory denial of beneficial treatment,"[23] federal agencies must contend with demands to
loosen research requirements. Related to such calls for relaxation
are concerns that certain populations, such as women and children,
have been systemically banished from protocols and thus cannot reap
benefits emanating from research. Furthermore, the practice of
experimenting with the desperately ill has fashioned favorable
views among clinicians and patients about therapeutic merits of
research. Regulators have responded by hastening the approval
process for promising treatments for life-threatening illnesses,
easing access to unapproved therapies, and allowing "desperate use"
guidelines for gene transfer research. Each of these regulatory
responses remove unproven interventions from the category of
"research" into that of "therapy" in certain circumstances.

Informed Consent and Its Flaws

The fundamental tenet of informed consent maintains
that research may not be performed "unless the investigator has
obtained the legally effective informed consent of the subject or
the subject's legally authorized representative."[24] Although the researcher must provide an
IRB-approved consent form, he may freely discuss the experiment
with the patient, explain terms employed in the consent form, and
address any queries of the subject without Board monitoring. As
noted in discussion of the Belmont Report, informed consent for
research is mandatory, yet its incompleteness or comprehensiveness
in therapeutic settings varies with the individual physician. In
the latter milieu, physicians are expected to attend only to the
welfare of the individual before them. The doctrine itself is
rooted in fundamental values such as autonomy, individuality,
bodily integrity, leading one commentator to note that
"[i]nformation is power and because information-sharing inevitably
results in decision-making sharing,...informed consent has helped
transform the doctor-patient relationship."[25] Other aims of informed consent include elevation
of rational decision-making, prevention of fraud and duress,
promotion of self-scrutiny by the physician-investigator, and
involvement of the public in significant issues of health care
research and policy. It aims to enrich the physician-patient
relationship in treatment decisions, envisioning an active patient
role made possible by informed consideration, deliberation, and
choice.

Informed consent, then, succeeds only when subjects
are fully apprised of the potential dangers they chance.
Regulations thus mandate that risks, benefits, and alternatives to
participation be described and that patients be advised of
procedures that would not be performed but for the
research.[26] Subjects are also to be told in lay language that
a project involves research and advised of the nature of privacy
protections as well as the appropriate person to consult with any
questions.[27] Additionally, researchers must clarify that
participation is voluntary and that refusal to participate will not
adversely affect the potential subject.[28]

One standard justification for such disclosure
obligations is that dangers of research cannot be ascertained in
advance. Experimental settings, "more so than those in which
standard medical treatments are dispensed, pose unknown...degrees
of risk...[so] there must be broad allowance for personal,
idiosyncratic preferences and values."[29] Since medical expertise by definition does not
exist in research contexts, patients possess no reason to defer to
it. No one proves a better expert than the patient in resolving the
core moral concern of experimentation, i.e. whether he should
volunteer his body to augment medical knowledge.[30] Furthermore, experimentation often confers little
or no gain upon the subject. Informed consent reflects a judgment
that most patients possess sufficient capacity to comprehend,
evaluate, and render decisions regarding their medical condition
and future. Unless evidence suggests otherwise, competence to
consent is presumed in most instances.

Numerous factors, however, work to undermine
patients' abilities to understand, balance, and render decisions,
diminishing their competency to consent. The process of informed
consent occurs at a time when unease often threatens to compromise
it. Illness can interfere with a subject's routine thought
processes and hinder him from reaching responsible conclusions.
This consideration proves all the more problematic when stress,
pain, side effects of drugs, or fear accompanies sickness.
Ramifications of an ailment itself may bring about diminished
competence, and physical and emotional consequences of illness may
additionally influence a patient's perception of information
disclosed. Clinicians, then, "may be justified in thinking that it
is foolish to approach any patient as a capable joint participant
in decision-making."[31] While problems in informed consent may well
emanate from inadequate or nebulous disclosure, shortcomings are
likely to arise due to the doctrine's failure to regard competence
as present in degrees, varying over time and under different
conditions. Federal regulations largely disregard the process by
which patients evaluate information presented to them and supply a
"generic presumption rather than specific criteria for assessing
competence."[32] Because it involves assessments of numerous
considerations, competence cannot be easily determined. To view
consent as fulfilled once information has been furnished proves
problematic, however, since it wholly ignores underlying processes
of deliberation.

Inability of the patient to comprehend that motives
of physician-investigators conflict with his own in the research
setting likewise seriously undermine informed consent's goals. The
presence of doctor-investigators in white coats may lead to
mistaken subject beliefs that research being performed is for one's
own benefit. Traditionally, the doctor-patient relationship has
been characterized as a fiduciary one premised on honesty,
confidence, and good faith. Notions that physicians in therapeutic
settings endeavor to achieve as much as possible for the individual
patient seeking medical assistance and that the professional's
recommendations are trustworthy endure. Patients' confidence in the
beneficence of physicians cause the former to regard invitations to
participate in research as "professional
recommendation[s]...intended to serve...individual treatment
interests."[33] This conviction hinders patients from appreciating
that in research, unlike therapy, the research question proves
primary:

Patients often fail to differentiate between
experimentation and therapy, and those with a poor prognosis may
esteem research as a treatment option. The manner in which a
physician-investigator presents the possible advantages of research
to a subject affects the degree to which the latter misconstrues
the nature of his participation in a study. Patients thus fail to
recognize that the "ideology of professionalism," which allows
doctors considerable discretion in rendering decisions for patients
due to faith that physician self-interest will succumb to patients'
interests, cannot be applied to clinical research situations since
physician-investigators harbor dual allegiances to subjects as well
as the research protocol. Medical professionals confront the
difficult dilemmas of seeking truth for science, beneficence for
the patient, and self-interest as an individual
investigator.[35]

Several other dynamics of the physician-patient
encounter likewise highlight deficiencies in the current
formulation of informed consent. Permeating the doctor-patient
relationship are authoritarian overtones; the assertion that
patients cannot comprehend esoteric medical information has often
been used to justify doctors' command over patient needs. Because
informed consent's underlying assumption- i.e. that patient
autonomy merits respect- has been alien to the physician mindset
throughout medical history,[36] the doctrine has not significantly tempered
physician authority in the decision-making process. Independence of
physicians has been preserved at the expense of patients. A power
differential exists even between the most decisionally capable,
sophisticated subject and an investigator, and inevitably "the
researcher is on top, and the patient-subject is on the
bottom."[37] This discrepancy is a product of a patient
weakened by disease and a researcher possessing a superior grasp of
the relevant medical knowledge. As an affliction grows more
serious, the power imbalance grows more extreme; worsening disease
yields desperation, which can render patients susceptible to
manipulation. Further aggravating this situation is the fact that
subjects are often recruited from different age and demographic
groups than researchers, typically from those enjoying less power
and economic status than investigators.

Such factors contribute to potential for those
holding knowledge to abuse their power, dismiss patients as
irrational, and thus justify paternalism and beneficence rather
than subject autonomy as controlling guides for research conduct.
Even physicians theoretically dedicated to securing patient consent
concede that, in practice, they exercise laxity in informed
consent. Their invitation to a patient to participate is a result
of an already completed, careful consideration of the project's
risks and benefits as well as their conclusion that no harm will
come to the patient. Thus, investigators may elusively address
patient concerns and suggest that participation is expected or that
nontrivial risks are minimal.

Differences between investigator and patient prove
so substantial that the former often fails to regard the patient as
patient, but rather only as a subject. Scientific dedication to
objectivity causes investigators' thought processes to become
objectified, transforming human beings under study into "data
points to be plotted on a chart that will prove or disprove a
research hypothesis."[38] As cancer researcher James Holland comments,

It cannot be doubted, however, that the majority of
Holland's patients seek a cure and regard him as their physician,
not merely as a scientist. In this scenario, then, the Declaration
of Helsinki's distinction between therapeutic and non-therapeutic
proves empty. Researchers additionally manifest objectivizing
tendencies in their interest in a new treatment's upshot in terms
of longevity, while patients often are harbor quality of life
concerns. Furthermore, objectification may grow more extreme
through influence of attitudes on race, creed, gender,
socioeconomic standing, and the scientific imperative of the
research.[40] It should also be noted that medical research
greatly differs from the doctor-patient relationship, traditionally
deemed a private, one-on-one concern. A physician-investigator
scarcely becomes acquainted with the patient-subject, and research
fellows, nurses, or non-physician associate investigators may
secure consent. The objectification process thus reinforces
diverging values which exist between physician and patient and
which may impact decision-making.

Aside from the aforementioned difficulties the
research setting poses for efficacy of informed consent, more
general shortcomings also present in the therapeutic context-
routinization and costs as well as difficulties of disclosure-
undermine the doctrine's goals. Legal medical ethicist Jay Katz
argues that in the clinical milieu, doctors have never accepted
informed consent as a route to recognizing patient autonomy,
instead merely tolerating it as a requisite legal duty:[41]

Such routinization endangers consent in an era when
it is most needed, i.e. when investigators oversell gene therapy
research to patients and the media. Consent is likewise jeopardized
due to its costs: the process proves time-consuming, and ensuring
that patients genuinely understand what a study entails and why
necessitates more effort than doctors believe they can reasonably
invest. Another difficulty emanates from the requirement that
professionals disclose alternatives. If the alternative is a
treatment that doctor does not recommend, uncertainty may surround
whether the option should be disclosed. Physicians often do not
wish to furnish patients and families with information concerning
experimental procedures, concerned that awareness of an alternative
to death is "inherently coercive."[43] Divulging alternatives may open patients to
situational coercion, leaving them incapable of exercising free and
informed choice because of societal pressure to exhaust all
possible measures. Thus, when no standard therapy exists, some
doctors prefer to promote acceptance of a fatal outcome rather than
to suggest experimental technology.[44]

Disclosure itself derives meaning from
investigators. Those deeming novel technologies "promising" rather
than "experimental" mold disclosure differently than those who
evaluate experimental procedures more cautiously. Disclosure also
proves problematic when a researcher provides too much information;
if asked to digest huge quantities of complex knowledge, a patient
will be overwhelmed rather than educated and cannot ask questions
because he does not understand enough even to formulate them.
Striking a balance in terms of the quantum of information to
disclose is difficult, for a doctor who reveals too little out of
concern for encumbering a patient may foreclose the latter's
ability to make decisions in which his needs are inconsistent with
that which the physician thinks best. Additionally, the situation
in which disclosure occurs merits attention. When consent is sought
under humiliating or insulting conditions, it cannot be labeled
"informed." The net result of aforementioned considerations is
generally "informed compliance" as opposed to informed consent:
doctors render decisions concerning the type of treatment patients
should have and then supply whatever information in whatever
setting is necessary for assent.[45]

The legal system's failure to afford effective
remedies to patients injured by inadequate informed consent further
contributes to the doctrine's impotence. Consent regulations
provide no adequate remedy to patient-subjects for a researcher's
or institution's breach. While subjects suffering harm in the
course of research due to a failure to obtain informed consent may
receive medical and psychological treatment from the institution,
regulations do little for victims of unconsented-to study. While
some argue that a private cause of action can be inferred from the
regulations,[46] no appellate court has addressed this possibility.
No court yet has provided recourse for infringement upon a
subject's right of choice without physical or emotional injury,
suggesting that current case law cannot sufficiently safeguard
subjects' rights to informed consent. Courts appear recalcitrant to
place sanctions on researchers who are experts in their fields and
endeavor to better medical and social science.

Whereas compensatory justice mandates that society
indemnify subjects for research-related injuries since they assume
a position of risk on behalf of society,[47] patients experience tremendous difficulty
obtaining legal redress since determining the scope of required
disclosure proves problematic for courts. To establish physician
negligence in obtaining consent, a plaintiff must demonstrate that
a patient-physician relationship existed, a physician had a duty to
disclose certain information, the physician failed to provide this
information, and the failure to do so cannot be excused. A showing
must additionally be made that if the professional had provided the
patient with the undisclosed information, the patient would not
have consented to treatment, and that the failure to disclose
constitutes the proximate cause of injury and damages
claimed.[48] Causation often is the most difficult element to
prove, established when the injured can demonstrate that he would
not have assented if proper disclosure occurred. Negligent
disclosure, furthermore, is determined in many states according to
a "professional standard." Disclosure is thus often viewed as a
concern of medical judgment, determined by what a reasonable
physician under the same circumstances would reveal.

Institutional Review Boards and Their
Shortcomings

Like informed consent, IRBs seek to safeguard the
welfare and rights of subjects. DHHS regulations mandate that
proposed clinical research undergo review of an IRB, a body which
determines whether and on what terms medical experimentation
involving human beings may be conducted. Boards function as peer
review committees ensuring that research studies are scientifically
sound, well-designed, safe, and that potential benefits outweigh
possible risks those under study. To perform such duties, these
bodies must be composed of members with sufficient scientific
expertise to appraise the research protocol as well as the
researcher's abilities. In reviewing experiment proposals, IRBs
must determine that dangers to the subject are minimized, selection
of subjects is equitable, risks are reasonable in relation to
anticipated benefits, appropriate informed consent will be secured
and carefully documented for each subject, and that if necessary,
the research plan will include monitoring of data.

Boards are expected to consider the nature,
content, and design of the study, ethical guidelines of the Belmont
Report, and where appropriate, the regulatory mandates of DHHS and
FDA.[49] IRBs also must conduct a continuing review of
every study at least annually as well as check the informed consent
document provided to each subject, ensuring it contains all factors
mentioned in federal regulations. They may, however, waive the
informed consent requirement for research entailing only minimal
risk if the waiver will not adversely impact subject rights and
welfare.[50] Boards additionally must also heed specific
regulations affording additional protections to research involving
vulnerable subjects, i.e. "children, prisoners, pregnant women,
[and] handicapped or mentally disabled persons."[51] Federal guidelines suggest that IRBs exercise
special caution in safeguarding the interests of these subjects by
including an individual "knowledgeable and experienced in working
with these subjects"[52] as one of its members.

Because IRBs act as representatives of the broader
local community acceptance of an experiment's particular
risk/benefit ratio, federal regulations also devote attention to
the composition and operating procedures of such bodies. IRBs must
consist of at least five individuals of varying backgrounds. One
must possess primarily scientific interests, one must hold
primarily nonscientific interests, and one must lack affiliations
with the research institution. A quorum, with at least one member
whose concerns are nonscientific, must be present for any vote.
Diverse membership aims to safeguard the rights and welfare of
subjects effectively; detailed rules additionally mandating that
"[e]very...effort be made to ensure that no IRB consists entirely
of men or entirely of women" and that more than one profession be
represented further this goal.[53] Lay members theoretically function as watchmen,
defending against excessive zeal of scientists and providing a link
with the norms of the local population. A majority of IRB members
rather than subcommittees or delegees, furthermore, must study
research proposals at regularly scheduled meetings. IRBs thus
reflect a judgment that medical progress should move forward, yet
without relegating the interests of human study participants.

IRBs as currently configured, however, protect the
institution and its investigator rather than shield research
subjects. The majority of the Board's members serve on the faculty
of the institutions to which the investigator belongs. Not only do
these individuals share concerns and objectives similar to those of
the investigator, but they also recognize that just as they now sit
in judgment of a research proposal, their own protocols will be
subjected to the same scrutiny. It thus proves improbable that
Board members will demand from other experimenters a standard of
disclosure and consent that insulates human research subjects if
doing so will tighten the conduct of research. IRBs therefore do
not address problems common to many studies, including inadequate
differentiation between trivial and non-trivial risks, manipulation
of subject consent, insufficient highlighting of the severity of
foreseeable risks and nondisclosure of their probability, scant
discussion of risks and benefits of non-participation,[54] and consent forms which inflate possible benefits
or are otherwise deficient.

Boards typically strictly focus on risk-benefit
ratios as well as on consent forms, rendering them less likely to
promote meaningful consent. Approved consent forms often do not
furnish relevant information in understandable language, and an IRB
that determines that research poses only minimal risk and
subsequently waives the consent requirement deprives the subject of
any role in deciding whether risks are minimal or of his desire to
be advised of possible trivial risks. Federal regulations thus
implicitly allow researchers and IRBs to choose when a prospective
human subject may exercise his autonomy.[55] Furthermore, IRB focus on consent forms and
requirements contribute to little evaluation of the merits of
research, a deficiency also attributable to members bearing
institutional loyalties who get caught between desires to safeguard
subjects and to advance their institutions. Composition of the IRB
itself likewise promotes institutional rather than subject
concerns, for dominance by researchers fosters a systematic bias
favoring experimentation. As Professor Robert Veatch explains, it
also proves difficult to involve a scientifically-dominated group
in assessment of whether a research protocol accords with standards
of community acceptance:

Additional shortcomings of IRBs emanate from
changes in the research environment as well as increased workloads.
The current framework for IRB practices was fashioned in the
1970's, when one investigator usually performed research and worked
under government funding with a small group of human subjects in a
university teaching hospital.[57] Contemporary experimentation, however, is quite
different due to increased commercialization and private funding of
research, explosion of managed care, use of multi-site trials, an
increase in patient consumerism, and escalating numbers of research
protocols.[58] Such changes have placed tremendous strains on
IRBs, which have acquired additional responsibilities and mountains
of paperwork. Boards must now grapple with complex novel issues
bearing significant societal implications, such as genetic
research. Resource constraints combine with these factors to render
IRB monitoring of a study's progress following approval virtually
nonexistent and to preclude Boards from going beyond their most
perfunctory requirements. Federal guidelines promote a rushed
atmosphere where thoughtful evaluation often proves impossible, and
Boards inundated with protocols and adverse event reports cannot
devote sufficient attention to each review.[59] These bodies rarely perform on-site monitoring of
research conduct, relying on an honor system. They are also largely
incapable of monitoring possible conflicts of interest of
researchers, a problem plaguing gene therapy experiments.

Aforementioned hardships facing IRBs contribute to
their inability to protect vulnerable subjects unable to defend
their own interests in the informed consent process. No national
consensus or consistent guidelines exist, for example, on what
constitutes proper safeguards for individuals with progressive
dementias such as Huntington's and Alzheimer's diseases.[60] Thus, cognitively impaired research subjects must
look to IRBs for protection. Consequently, Boards should devote
special care to considering the nature and degree of impairment,
prospective risks and discomforts of participation, and the
potential for direct benefit to the individual subject. Increased
workloads, resource constraints, and problems created by
institutional loyalties, however, preclude IRBs from making such
careful determinations. Significant evidence suggests, for example,
that Boards are unlikely to compensate for the lack of particular
regulations pertaining to the cognitively impaired through a
proactive use of their discretionary authority.[61] IRBs do not review the details of
investigator-subject interaction, thus depriving groups especially
vulnerable to coercion of much-needed protection and devoting
inadequate attention to these groups' assumptions of trust in
physician-researchers.

The Terminally Ill

Federal regulations do not classify the terminally
ill as a vulnerable population, yet thorny consent issues arise
from the fact that many research subjects are vulnerable merely
because they are ill. Individuals suffering from malignant
disorders or plagued by ailments refractory to other treatment
often desperately seek inclusion in clinical trials evaluating the
efficacy of novel drugs and drug combinations as well as of
uncorroborated practices. Vulnerability of such patient-subjects
varies with the gravity of illness as well as their degree of
desperation. Cancer and AIDS, for example, arguably are the two
most feared ways of dying in the developed world, "perceived not
just as lethal, but as dehumanizing, literally so."[62] A terminal diagnosis itself shapes what
researchers as well as patients regard as reasonable, both often
believing that the dying person has "nothing to lose." In
confronting certain illnesses, it additionally proves impossible
for a researcher to render the requisite boilerplate language of
the federal regulations candidly, as experimental therapies are the
only available treatments and refusal to participate without
penalty, i.e. imminent death, is impossible. Even if consent forms
possess clarity and accuracy, conversations with patients may
render issues nebulous. Desperately ill subjects may selectively
listen, absorbing only facts about prospective benefits, and
investigators anxious to recruit volunteers may address risks in a
cursory manner. Dying persons thus may not truly be "free" to
render autonomous decisions, captive to their disease and thus
under coercion of their illness and potentially of others. As a
former editor of TheNew England Journal of Medicine
observes, "the thumb screws of coercion are most relentlessly
applied [to] the most used and useful of all experimental subjects,
the patient with disease."[63] Likewise, as a one's disease grows more severe,
his capacity to retain information from the consent procedure
decreases.

Diagnosis of a terminal illness usually spurs a
significant psychological reaction in patients and sometimes causes
a variety of psychopathologies.[64] Physiological symptoms may exacerbate
psychological hardships. This combines with patients' reluctance to
question their physicians to reduce the capability of a terminally
ill patient to engage in autonomous, rational decision-making.
Cancer patients, for example, commonly experience sentiments of
inadequacy, fear, anxiety, confusion, and hopelessness, dreading
the "six D's:" dependency, death, disfigurement, disability
interfering with normal life functions, disruption of
relationships, and discomfort or pain resulting from the disease.
Their disease itself may directly hinder cognitive ability:
fatigue, toxicity of medication, and recovery from radiation can
impair the speed and quality of thought processes. One who is
hospitalized for an extended period of time may additionally
respond to his environment in a manner hindering his ability to
render informed decisions. Sleep deprivation commonly associated
with hospital stays, for example, exaggerates the emotional and
physical trauma of terminal illness and may create confusion,
disorientation, and memory disturbance.[65] Just as prisoners prove wholly dependent on guards
and other jail employees for their well-being, the terminally ill
often depend completely on hospital staff and researchers.
Consequently, such patients endeavor to gain favor with researchers
and to eschew behavior they fear might provoke retaliation.

While such environmental and psychological
difficulties may make it virtually impossible to balance logically
the advantages and disadvantages of participating in potentially
hazardous research, concerns also arise that the dying, having
abandoned all hope, may assent to immoral or unduly unwise
experiments when experimenters exploit potential subjects' despair
or incapacity. Oncologists, for example, justify employing
countless approved drugs for unapproved uses with claims that they
are simply responding to the desires of their dying patients. But
as one physician to cancer patients remarks,

Depression may likewise contribute to willingness
to consent, rendering the significance of risk meaningless. Such a
"nothing to lose" attitude among experimenters, however, proves
most problematic: patients confronting imminent death are real
people, not objects, who may treasure quality of life over its
length. When a researcher deems a study useful or necessary, he may
opt not to scrutinize the act of consent for fear of losing
precious research resources.

Respect for autonomy superficially suggests
that the desperately ill should be afforded considerable freedom to
consent to experimental study participation. The terminally ill
stress liberty to control one's body, a particularly acute concern
when no alternative treatments to investigational therapy exist.
Autonomy, however, is not absolute; drug regulation involves a
dilemma between the competing concerns of scientific validation and
individual choice. FDA thus faces the nettlesome task of weighing
societal goals against each person's freedom, for every time access
is broadened, science is jeopardized.[67] Patients willing to forego thorough scientific
validation of a treatment are denied access, yet selecting a course
of treatment is an important consideration for the seriously ill.
Traditional FDA policies require that a drug be proven safe and
effective prior to distribution in interstate commerce and bar
access to investigational therapies for noninvestigational ends. To
respect autonomy more effectively, however, the Administration has
allowed the sale of certain drugs still under investigation for
AIDS patients and has promulgated regulations allowing marketing of
drugs of unknown safety if benefits appear substantial. Such
policies reduce the length of time necessary to test drugs for
severely debilitating diseases, have revolutionized access to novel
treatments for life-threatening diseases, and minimize differences
between access to experimental drugs and to investigational
procedures.

This vindication of autonomy, however, forces
doctors as well as patients to render difficult decisions in the
absence of substantial information. More troubling is that FDA's
loosening of its drug approval procedures partially emanates from
compassion toward those unable to survive long enough to wait for
exhaustive testing of new therapies. Compassionate motivations can
interfere with the furnishing of information and preclude
straightforward conversations between patient and experimenter
about the reasonable likelihood of success. They additionally may
bury the character of an intervention and sacrifice the
researcher's complete consideration of the project at hand. Most
significantly, however, they further obscure the "profound
difference between the scientific alliance between researcher and
subject and the therapeutic alliance between doctor and patient,"
rendering the distinct roles of each party to these relationships
"indistinguishable."[68]

Just as the compassion argument proves flawed,
scrutiny of experience with the drug AZT displays significant
shortcomings of claims for greater access to experimental therapy
premised upon autonomy and highlights the need for research
performed in a systematic, scientific manner. AIDS is seen as an
illness in which there is no distinction between experimentation
and treatment since no cure exists. The disease overwhelmingly
plagues the young, hastening a premature and certain death. Many
afflicted thus are willing to disregard dangers associated with
experimentation for even remotest chance of therapeutic gain. In
the absence of alternatives, the importance of individual autonomy
appears to supercede the government interest in safeguarding
overall health. As AIDS activists clamored for increased access to
experimental therapies, the public began to appreciate the tangible
benefits research participants enjoy, including possible
therapeutic advantages when other treatments prove ineffective,
contact with eminent physicians, and careful monitoring of one's
disease. Participation in clinical trials came to be regarded as a
boon rather than a bane against which to be protected, further
blurring the line between research and therapy. ACT-UP's slogan, "A
Drug Trial is Health Care Too," indeed encouraged AIDS victims to
procure experimentation as treatment and researchers to deem AIDS
patients potential subjects with nothing to lose. FDA bowed to
pressures to expand access as well as to hasten new drug approvals,
granting AZT fast-track treatment since initial studies suggested
it was effective in combating AIDS.

Later evidence, however, demonstrated that this
highly toxic substance with dire adverse effects cannot be
tolerated by many patients and may furnish only fleeting benefits.
Merely four of one hundred patients experience a slower progression
of the disease,[69] meaning that FDA's allowance of greater access to
AZT may have caused many to rely on a substance not nearly as
efficacious as initially promised. If, as with AZT, patients pin
hopes on the first drug to offer promise, they may sacrifice other
innovations altogether. Absent a subject population to test the
safety of alternative potential cures, new treatments cannot be
established unless the initial treatment is clearly ineffective.
The AIDS epidemic additionally evinces that the dangers of
experimental drugs cannot be overemphasized: unofficial trials
involving an ingredient known as Compound Q lacked safeguards such
as an IRB and resulted in numerous fatalities.

The AZT story likewise demonstrates the difficulty
of securing informed consent due to the blurring of the research/
therapy line. Terminally ill patients advised that medicine cannot
offer them any hope come to regard experimental protocols as
treatment. Instead of approaching experimentation with skepticism,
they may demand access to such interventions as a right; in such
instances, informed consent affords no profound protection.
Terminally ill research subjects commonly fail to comprehend that
they are participating in research that may not be intended
primarily for their benefit, a phenomenon termed the "therapeutic
misconception." Self-deception in viewing experimentation as
treatment, particularly evident in terminally ill cancer patients,
proves readily apparent in Phase I drug studies with anticancer
agents. FDA regulations state that such investigations are not
intended to possess any therapeutic content, yet the National
Cancer Institute labels them "potentially therapeutic." [70] Furthermore, nearly any intervention can be
portrayed as "potentially therapeutic," transforming nonbeneficial
studies such as Phase I trials, in which 94% of investigators agree
their patients enroll "mostly for the possible medical
benefit,"[71] into therapy. Deception enables researchers as
well as subjects to "double" themselves, the former seeing
themselves as physicians and the latter deeming themselves
patients.[72]

When the physician and researcher are embodied in
the same person, it proves unlikely that patients can ever
distinguish between these two conflicting roles, unable to fathom
that their doctor would consciously employ them as a means for his
own ends. Physician-investigators have long asserted that clinical
research and therapy are inextricable, that drugs and therapies
they scrutinize in scientific studies could be offered to patients
in scientific settings, and that the sole distinction between their
research and clinical endeavors lies in the objective evaluation of
effectiveness and risk-benefits to which they submit their
interventions.[73] Many likewise maintain that patients are exposed
to unscientifically proven, ineffective, and potentially hazardous
therapies in clinical practice, about which patients learn little
since their doctor believes in these therapies and many other
professionals share their physician's unsubstantiated beliefs.
Clinical research, investigators posit, differs from therapy solely
in that it seeks not to perpetuate scientific unknowns, but to
resolve uncertainties. To the extent that patient-subjects assume
that physician-researchers act in their best interests, then,
informed consent constitutes little more than a fiction. For the
terminally ill who do attempt to ponder the risks of research,
their decision-making capacity is nevertheless impaired by the
psychological and physiological effects of their sickness.

"Our quest for a formula that will banish death
seems to make it acceptable to try questionable regimens on
the...terminally ill...Those who insist on using the dying as
experimental subjects...see death as abnormal and dying patients as
subhuman."[74] We must cease treating the terminally ill as
subhuman by offering them dubious experiments under the guise of
therapy. Such an offer cannot be justified by their demands for
autonomy or by our belief that knowledge gained will benefit
mankind. Researchers who believe their subjects have "nothing to
lose" by participating in experimental studies should be
disqualified from performing such research, for they are unable to
protect the welfare of their subjects adequately. Similarly,
subjects harboring the same sentiments and desperate due to their
malady should be disallowed to participate since they cannot
furnish competent, informed, and uncoerced consent.

Despite their nonmention in federal regulations,
the terminally ill arguably constitute our most vulnerable
population and need many more safeguards than currently provided.
Not only should federal regulations explicitly classify the
terminally ill as a vulnerable population, but research on this
class should also be prohibited unless it potentially offers
therapeutic benefits to individual subjects. Patients should
receive confidential psychological evaluations prior to
participation in studies, IRBs should be required to consult with a
representative devoted to safeguarding their rights, researchers
should be trained to recognize the psychological troubles plaguing
those facing imminent death, and subject advocates should be
available to assist the terminally ill during the informed consent
process.[75] The terminally ill share several characteristics
of other vulnerable populations: like children, their ability to
make informed decisions is frequently impaired, and like prisoners,
they are "captives" of their sickness, the hospital, and their
doctor. Absent explicit regulatory classification of the terminally
ill as vulnerable, numerous researchers and IRBs will disregard the
susceptibility of the terminally ill. Even those scientists who
appreciate vulnerability of their patients may not take adequate
care to respond to the particular psychological trauma that a
terminal diagnosis causes.

Recognizing the frangibility of the terminally ill
would hardly impact the rapidity with which research is conducted
and thus would not significantly lessen the societal benefits of
such research. General regulations applicable to vulnerable
populations are essentially unobtrusive for IRBs and researchers
alike.[76] Categorizing the terminally ill as vulnerable
likewise will not endanger their autonomy and dignity. Rather, it
will demand they be regarded as complete individuals battling the
psychological effects of their illnesses, but who are entitled to
render their own informed decisions. Regardless of agreement with
the aforementioned proposals on how to protect the terminally ill
more effectively, one must concede that scrutiny of this class of
subjects emphasizes that "[i]nevitably, regulation of human
research involves tradeoffs between the personal autonomy and
rights of research subjects, potential benefits to society, and the
need to prevent research abuse [and that] [r]easonable
people...differ as to how this balance should be struck."[77]

Women

Whereas the terminally ill suffer from
underprotection, women have traditionally been disadvantageously
overprotected and systematically excluded or underrepresented in
clinical research studies. Because of their reproductive
capabilities, women and their potential fetuses have been regarded
as meriting safeguards from the possible hazards of
experimentation. This policy of fetal protection, opines one
author, results from "intellectual lassitude, defensive legalism,
and a misplaced sense of obligation."[78] Researchers routinely deem female subjects more
vulnerable than male ones and assume that unvalidated treatments
present unique reproductive hazards to all women. They frequently
label pregnant individuals incapable of effectively weighing risks
to a fetus against their own well-being and therefore deny these
women the chance to participate in studies, regardless of the true
level of risk involved. Research protocols typically ostracize
nursing and pregnant women as well as females of childbearing age;
the few that welcome pre-menopausal women strictly regulate their
reproductive activities. Recent GAO investigations reveal that
numerous clinical trials funded by the NIH "were designed to
include women, but not in numbers high enough to allow analysis
that would definitively measure different outcomes for men and
women."[79]

The assumption that female physiology diverges from
the norm has proven damaging in medical research, for it deems
results accurate only for (white) men scientifically acceptable and
thus perpetuates the practice of banning women from clinical trials
for the sake of simplicity. Researchers often posit that the male
body is less complex and that it is therefore easier to study men
and generalize findings to women rather than to perform research on
women directly. One study on links between obesity and breast as
well as uterine cancer, for example, employed only male research
subjects since experimenters believed their work could be performed
more rapidly on nonmenstruating individuals. Another study on the
effects of aspirin in reducing heart attack likewise involved
twenty-thousand males yet no females. Desires to conduct studies
with homogeneous populations and concomitant concerns for
cost-effectiveness repeatedly have been offered as justifications
for passing over groups other than white men in medical research.
Perceptions of the middle-aged male as the common breadwinner and
stress on the economic costs of health care may also have
contributed to overemphasis of concern on men's health. Researchers
likewise label women unreliable, unlikely to follow through with
research protocols because of child care demands or because they
may become pregnant. As policymakers as well as researchers
prioritize issues resounding with their personal concerns, it
proves additionally problematic that in a scientific community
which "funds what it fears," women comprise a minority of medical
researchers and a minute percentage of those making funding
decisions.

These general rationales for excluding and
underrepresenting women do not withstand scrutiny. It defies
logical consistency to contend both that women are different from
men due to their hormonal cycle as well as their ability to become
pregnant and that females are similar enough to males to apply
clinical research findings gleaned from studying the latter easily
to them. Furthermore, the practice of generalizing findings to
women undercuts their unique health care needs, for some illnesses
manifest themselves differently or exclusively in women. An
additional shortcoming of the protectionist rationale is that it
assumes an adversarial relationship between a woman and her fetus,
premised upon the belief that fetuses necessitate protection from
their carriers. It consequently destroys a woman's right to control
her pregnancy as well as her decision-making freedom.[80] Experimenters have long offered potential
pregnancy, however remote, as a rationale for banishing all women
from research protocols, yet automatic exclusion without
substantiation of harm to the pregnant individual is unnecessary.
Drop-out rates likewise can be factored into any study. More
effective methods to achieve homogeneity, furthermore, exist; use
of gender and race to obtain this end are simplistic, weak proxies.
AIDS research, for example, reveals that accurate indices of
homogeneity include defining a range of T-cell values or other
virologic and hematologic abnormalities characteristically
associated with the illness.[81]

Such general exclusionary rationales may prove
flawed, yet drug trial sponsors frequently cite possible exposure
to tort liability as a rationale for eliminating women from trials.
The primary source of concern lies in fear of potential damage to
offspring, a result of the Thalidomide debacle of the 1950's in
which thousands were born with birth defects and many stillbirths
occurred.[82] The next decade saw discovery of complications of
DES, which caused many daughters of women who had taken the drug to
develop reproductive abnormalities as well as a heightened risk of
vaginal cancer. Suits brought by these offspring proved costly to
the pharmaceutical industry, provoking protectionist policies which
in turn ironically hurt those intended to be safeguarded. Whatever
liability risk exists in research, however, may be contained
through informed consent. Judicial precedent demonstrates that
without other negligence, informed consent acts as a shield against
liability. Warnings, including disclosure of possible harms to the
fetus, furnished during the informed consent process both maximize
autonomous decisionmaking and minimize chances of recovery in tort
actions for research injury. Additionally, the low incidence of
such injury nearly eliminates likelihood of liability
imposition.

Chances for liability are indeed minimal. The most
notable instances of liability involving women as experimental
subjects turned not upon effects on offspring, but upon failure to
secure subjects' informed consent.[83] Only three reported cases implicate alleged
research injuries to offspring resulting from clinical study
participation, and in all instances, pregnant subjects did not
consent to participate in research.[84] Such precedent thus does not delineate the
boundaries of liability for harm to children when a woman has
legally consented to participate in a clinical study. It
additionally proves unclear whether securing a mother's consent
suffices to eschew liability for injury to offspring, for an unborn
child does not possess the capacity to consent. While one cannot
deny that trials must be meticulously crafted with tort liability
in mind, "the search for a cure simply cannot exclude
women."[85]

Ironically, banishing women from clinical studies
may in fact expose drug manufacturers to liability.[86] Liability for exclusion may occur when a woman
takes a drug untested on her sex which proves more hazardous or
less efficacious in females once marketed. Case law indicates that
insufficient study constitutes grounds for imposing liability
according to negligence and strict liability principles.
Manufacturers face strict liability due to defective product
design, and deficient testing may be deemed a design defect.
Manufacturers likewise must warn about predictable risks that
should be known, a requirement that can be met only with
sophisticated product testing. Claims that a drug is unavoidably
unsafe may be undercut if it is not tested on women but has
damaging results, and liability can attach from lack of data
requisite to determine appropriate protections for treatment of
women. Clinical trial sponsors thus cannot eschew tort liability by
omitting women in their childbearing years from protocols,
rendering decisions to exclude these women from studies or to
ignore the possibility that they may become pregnant while taking a
marketed drug dangerous.[87]

Depriving women of access to clinical research and
treatment additionally fuels possible charges of gender
discrimination, for the Supreme Court has fortified a woman's
prerogative to make choices affecting reproductive status.[88] Recognition in UAW v. Johnson Controls,
Inc. ,[89] a Title VII challenge to a fetal protection
workplace policy, that diverging applications of privileges to the
sexes constitute gender discrimination and that choices affecting
future children are rightly made by those who conceive and bear
these children provides a foundation from which to attack
differences in clinical research premised upon sex. Court rejection
of fetal safeguarding bolsters the claim that prohibiting female
participation in experiments for reproductive reasons is
discrimination against women as women.[90] Possibility of liability for banning female
trial participation again highlights an evolving view of
participation in research as a benefit, if not a right, presenting
nontrivial opportunities for direct medical gain.

Blanket exclusion of women from clinical trials
must be labeled unconscionable because of the severe harm it works
upon countless women. Physicians wishing to prescribe to female
patients drugs untested on women are left to guess at appropriate
dosages, possible side effects, and efficacy. Post-marketing
studies of drugs are not required to secure drug licensing, meaning
that women serve as marketplace guinea pigs, experimented upon by
their doctors.[91] Furthermore, the virtual absence of female
participants in medical research yields a general scarcity of
information pertaining to women's medical care and consequently of
knowledge crucial to their health and well-being. Doctors are
sometimes slow to appreciate hazardous drug combinations for women-
one example being the disproportionate occurrences of dangerous
heart rhythm abnormalities that concomitant use of Seldane and
erythromycin or ketoconazole causes - for a mere 15% of published
research contains any analysis of the differences in results for
women and men.[92] Knowledge of a drug's effects upon the expectant
mother's unique physiology is likewise crucial for healthy
pregnancies. Treatments that can save or extend her life, if
endangered, may furnish the sole opportunity to protect the life of
her fetus. The consent process affords the pregnant individual an
opportunity to render informed, free decisions, thus promoting
equality, autonomy, and self-determination in research as well as
reducing manufacturers' likelihood of facing successful liability
claims.

More fundamental, however, are the troubles
emanating from employing the male body as a reference for judgments
about the average individual. The practice renders the female
experience of menstruation, hormonal cycles, and pregnancy
exceptional rather than commonplace.[93] Disregarding material variables which entangle
homogeneity may infiltrate studies with significant error, yet
women desire and require accurate information about illnesses and
conditions which afflict them. Such information can also promote
women's health in general. As research enables us to enjoy
healthier lives, and healthier individuals are better able to
develop their capacities and talents, health can be regarded as
none other than a first-order need.[94]

The effect of the AIDS epidemic upon the female
population also vividly illustrates the importance of
gender-specific information. Failure to include adequate numbers of
women in clinical studies of HIV and AIDS has detrimentally
impacted the health of females suffering from the illness. When
women have been at the center of AIDS research, it is usually to
determine the most effective manner to bar or mitigate transmission
of HIV to a fetus, rather than how to best treat gender-specific
manifestations of HIV. It thus proves unsurprising that women
suffered grave side effects when given AZT dosages calibrated to
the 70-kg male. Furthermore, those who fit the Center for Disease
Control's "AIDS profile" receive timely Social Security benefits,
yet the CDC's definition of AIDS relies on symptoms present in men.
Women suffering from HIV experience a variety of recurring
gynecological disorders, including cervical cancer, pelvic
inflammatory disease, and chronic yeast infections, yet the CDC
definition does not reflect these symptoms.[95] Thus, many women with severe HIV-related
disabilities do not qualify for needed benefits; roughly 65% of
females dying from HIV-related illness do not meet the CDC
definition.[96] Women diagnosed with AIDS search in vain for
treatments designed specifically to mitigate the disease's effects
on the female body, causing females to be the fastest growing group
of those dying from the illness. In light of the rapidity with
which women aged twenty-five to forty-four- i.e. of childbearing
age- are acquiring AIDS, it proves crucial that women not be denied
the benefits of research.[97] Not only does exclusion deprive individual
infected women of their sole chance to prolong life, but it also
endangers the welfare of potential offspring.

Rectification of women's traditional exclusion from
AIDS research as well other clinical trials additionally demands
that special attention in the informed consent process be given to
issues particular to women. If the basal goal of consent is to
enhance self-determination of research subjects, disclosure of
information as well as assessment of voluntariness cannot involve
one monolithic standard. For women, experimenters must adopt a
standard that accounts for stereotypes of women as incapable, less
able, or untrustworthy decision-makers and that resists gender
norms fostering female subordination. Women often defer to
physician authority and do not wish to appear impolite. Older women
are especially accustomed to paternalistic relationships with their
physicians, while socioeconomically disadvantaged women as well as
those of color may not view themselves as autonomous agents, thus
reluctant to ask questions, voice concerns, or assert
themselves.[98] Women of color are often viewed as poor
decision-makers and thinkers: a physician asked about his failure
to secure consent from Mexican-American women participants in a
contraceptive study involving the possibility of receiving placebos
replied, "If you think you can explain a placebo test to women like
these, you never met Mrs. Gomez from the West Side."[99] More generally, a Commonwealth Fund survey
indicates that one in four women report being "talked down to" or
treated like a child by a physician, as compared with only 12% of
men. Likewise, 17% of women have been told a medical condition was
psychosomatic, whereas only 7% of men have been offered the same
diagnosis.[100] A researcher seeking women's consent must
recognize that they may fear coercion or ridicule and find
participation problematic due to family responsibilities. Such
matters must be addressed by NIH and FDA policies if medical
research truly is to embrace women.

Recent NIH reforms resulting from the 1993
Revitalization Act have greatly ameliorated research policies
pertaining to women. All applications for both intramural and
extramural research must now include women as subjects. The Act
additionally mandates that valid analysis be performed to
demonstrate whether variables under scrutiny impact subpopulations
and the sexes in varying ways. NIH guidelines state that:

The chief requirements for valid analysis are that
allocation of women and men to the intervention as well as control
groups occurs by a neutral process such as randomization, that
researchers perform impartial evaluations of the results of
studies, and that unbiased statistical methods be employed to gauge
and compare intervention effects among the genders. NIH guidelines
additionally delineate when women may and may not be prohibited
from participating: cost is not an acceptable justification, and
exclusion cannot be substantiated "unless a clear and compelling
rationale and justification establishes to the satisfaction of the
relevant institute...that the inclusion is inappropriate with
respect to the health of the subjects or the purpose of the
research."[102] A trial may include only one sex if the disease
or disorder being studied is gender-specific; in all other
instances, experimenters are to use roughly equal numbers of men
and women. Such an approach promotes gender justice, striving to
furnish women with beneficial medical knowledge and aiding them in
enjoying healthier lives. The 1993 reforms likewise demand that a
data system for collection, retrieval, and dissipation of knowledge
on women's health research which NIH supports be established.

NIH publication of an Outreach Notebook to aid
scientists in complying effectively with new guidelines also
deserves commendation, for it offers tips on how to include women
as well as on recruitment tactics. Guidelines recommend

establish[ing] a relationship...[which]
represent[s] a thoughtful

and culturally sensitive plan of outreach and
generally include[s] involvement of other individuals and
organizations relevant

to the populations and communities of
interest...The objective is

to establish appropriate lines of communication and
cooperation to build mutual trust and cooperation such that both
the study and the participants benefit from such
collaboration.[103]

The Notebook warns researchers that issues of
coercion prove especially important in dealing with female
subjects. Attention to cultural concerns as well as to the
importance of establishing mutual trust additionally evince respect
for women and will work to mitigate many of their reservations
concerning protocol participation. NIH recommendations likewise
stress that researchers should exert special effort to ensure that
women are fully informed and issue free consent. They also alert
researchers to constraints such as child care, which may affect the
ease with which women of differing ages and socioeconomic statuses
can participate. Such concerns explicitly acknowledge and
legitimize women's experiences,[104] previously unrecognized or used to justify
female exclusion. NIH regulations have been written into law, and
the Departments will no longer fund any projects failing to comply
with new policies on the inclusion of women. Researchers,
furthermore, must report yearly on gender of enrolled study
subjects. While such advances bode well for the future, a recent
New York Times article discouragingly reports that medical
researchers who secure federal dollars now generally include women
as subjects yet disregard the requirement to analyze the effects of
novel drugs on them.[105]

While NIH has moved from encouragement to
requirement with respect to female clinical trial participation,
FDA has merely moved from banishment to encouragement. 1977
guidelines provided that pregnant women or those at risk for
becoming pregnant should be excluded from Phase I studies and
further exhorted that those of childbearing potential be banned
from large-scale clinical trials until FDA animal reproduction
tests were performed. Only if sufficient information on the
effectiveness and safety were amassed during Phase II could women
of childbearing potential, defined to include those using
contraception, lesbians, celibate individuals, and wives whose
partners had been vasectomized, be included in further protocols.
FDA too issued new guidelines in 1993, stating that subjects in a
clinical trial should reflect the population that will use the drug
once marketed and suggesting that subjects include men as well as
women to allow for comparative analysis.

The new guidelines, however, do not require that
women be included in early drug trial phases. They demand that
scientists secure informed consent from women, warn participants to
take necessary measures to prevent fetal exposure to potentially
hazardous drugs, and furnish information about risks of fetal
toxicity. Nevertheless, guidelines still maintain that large-scale
exposure of women of childbearing potential should not occur until
results of animal toxicity tests are scrutinized.[106] FDA regulations additionally contain provisions
hindering the ability to render changes in drug research
procedures: these hortatory guidelines, which state that the
Administration sees no need to mandate that women be included in
specific trials, do not necessarily affect drug approval. Mention
of the need for more extensive research in drugs and devices that
might particularly benefit women is absent, as are details as to
what comprises sufficient representation of women in protocols. FDA
offers no counterpart to NIH's recognition of women's health
experiences, ignores problems of drawing women to research
participation, and fails to extend outreach programs to aid
scientists in including females.[107] The Administration does, however, alter its
former policy of eliminating women of childbearing potential from
studies, reasoning that determinations of fetal risk are "properly
left to patients, physicians, local IRBs, and sponsors..."[108] This appreciation of women's competence to issue
informed consent is a noteworthy improvement, though undue emphasis
is still placed upon the fetus.

Children

FDA policies have not safeguarded children
adequately; while no drug can be approved prior to extensive tests
in adults, drugs administered to children are approved regularly
without pediatric testing. Over two-thirds of drugs sanctioned for
use in the United States have not been tested in children,[109] despite the fact that many of these substances
are regularly prescribed to them. Studies indeed indicate that
merely 42% of drugs frequently used to treat children have been
tested on pediatric subjects in clinical trials.[110] FDA perpetuates this situation with its
"Pediatric Use" regulation, permitting manufacturers to escape
pediatric testing in cases where the drug will not be marketed
specifically for children if they affix a warning on the drug's
label stating that "[s]afety and effectiveness in pediatric
patients have not been established."[111] As FDA regulates drug manufacturers rather than
physicians, doctors are free to prescribe drugs to youngsters
despite the fact that they have not been tested in children.
Likewise, no requirement exists that a physician secure informed
consent for off-label use of drugs, meaning that children are left
to the whims of physicians' discretion to advise them or their
parents that they are receiving substances whose pediatric efficacy
remains uncertain.

Dearth of testing in children proves significant
since youngsters, whose physiology differs immensely from their
seniors, do not absorb drugs in a manner identical to adults.
Doctors may thus prescribe drugs in inappropriate dosages or may
opt not to prescribe potentially beneficial yet untested drugs at
all. While FDA may argue that pediatric testing will nevertheless
occur as a result of market forces, minute market size and lack of
profitability of adding a pediatric use to a drug label do not
motivate drug manufacturers to alter current practices.[112] It should be noted, however, that FDA recently
proposed to require manufacturers to collect and record pediatric
data.

The proposal, though, prompts consideration of
unique difficulties of informed consent which arise with children.
Surrogate consent is necessary for protocols involving children.
That of both parents is required where research implicates a
greater than minimal risk with no chance of direct benefit to the
individual child but proves likely to produce general knowledge of
the subject's illness. Both parents must also consent if
experimentation is not otherwise authorizable yet presents an
opportunity to understand or mitigate a grave health problem
affecting children. Youngsters themselves generally must "assent"
to participation, yet regulations appear to bestow unrestrained
authority to consent to their child's participation in research
upon parents of small children unable to assent.[113] Parents, however, may be unable to isolate and
safeguard an individual child's safety and dignity. In the "Baby
Fae" case, for example, a dying child received an experimental
baboon heart transplant. While the patient's mother consented, the
procedure stands as a disheartening instance of a mother swayed by
her child's forlorn situation. Even if consent was voluntarily and
consciously given, it should never have been requested.[114] Surrogate consent proves nettlesome because one
can never ascertain with certainty if the parent's decision is
proper, i.e. loyal to the child's best interests and desires, if
known. Those lacking capability to consent should not be coerced
into altruism by way of their surrogates' choices, and "proxy
consent," which fosters an image of a powerless research subject,
amounts to little more than a contradiction if consent seeks to
exalt self-autonomy and self-determination. Willingness to accept
proxy consent reflects our dilemma between devotion to individual
dignity and utilitarianism: when forced to compromise the former to
permit "needed" experimental procedures and trials, we hide the
tradeoff and profess enduring respect for the value which was
subordinated.[115]

Prisoners

Concerns for human dignity and capacity to consent
underlie the severe regulatory restrictions on conducting research
on prisoners, ideal subjects not only for cost control reasons but
also since life "is subject to few variations...[and] [t]he
imposition of experimental procedures that might inconvenience
free...subjects is not a burden on [them]."[116] Prisoners comprise a vulnerable population as a
physically healthy, captive group ideal for studies necessitating
constant monitoring of subjects as well as rigorous control over
diet and activity. As demonstrated by the oft-cited prison research
case of Kaimowitz v. MI Dept. of Mental Health ,[117] prisoners may grapple with constraints due to
their incarceration which impact their capacity to render truly
uncoerced and free consent. The Michigan Circuit Court confronted a
situation in which the patient had signed a consent form permitting
experimental psychosurgery, and two committees had reviewed the
consent process as well as the study. Holding that the procedure
could not be performed even with the prisoner's consent, the Court
judged the consent suspect partially due to the "inherently
coercive atmosphere" of the institution.[118] It additionally commented on the precariousness
of psychosurgery, adamant that "psychosurgery should never be
undertaken upon involuntarily committed populations, when there is
a high-risk low-benefits ratio" and raised concerns about
bargaining power imbalances in the prison scenario.[119] Situational coercion proves problematic since it
constrains the prisoner's freedom to render choices.

Compounding such difficulties is the message of the
penal system- one which may be offered to exonerate
experimentation- that prisoners necessitate reform and
reshaping.[120] If prisoners regard themselves as requiring
alteration, they may judge a hazardous "reformatory" experimental
procedure in their best interests. One commentator notes, however,
that "the applicability of ethical principles should not depend on
the participants' willingness...to take particular risks any more
than a person's agreement to be a slave justifies
slavery."[121] Although regulations require that incarcerated
persons be clearly informed that participation will not impact
parole opportunities, concerns nevertheless remain that prisoner
motivation to consent may emanate from the hope of appearing more
favorably before a parole board.

Prisoners are additionally protected in the
regulations through explicitly prohibited inducements. Their
participation may not be secured through advantages in living
conditions or chances to accumulate earnings to a degree that would
interfere with their "ability to weigh the risks of research
against the value of such advantages in the limited choice
environment of the prison."[122] Holmesburg Prison studies which University of
Pennsylvania scientist Albert Kligman performed demonstrate
problems of inducement confronting prisoners. Tests involving
prisoners helped formulate Retin-A skin cream, yet former inmates
complain that they were not informed of possible long-term effects
of the trials and were exploited and lured into participation
through pecuniary means. One explains:

Guidelines for research involving prisoners do not
merit criticism, however, because they place significant
restrictions on the use of a vulnerable population in research yet
afford the group the right to participate. For research implicating
incarcerated individuals, IRBs may approve protocols only if
researchers offer no questionable incentives to participate,
dangers of participation would be acceptable to a free volunteer,
pertinent information is furnished in understandable language,
subjects are selected equitably, and prisoner participation does
not bear upon parole decisions.[124] A majority of IRB members must also lack ties to
the prison from which human subjects are drawn, and at least one
member must include a prisoner or prisoner representative with
applicable background knowledge and experience.[125] While regulations do not fully eradicate
coercive forces present in prisoner decisionmaking, they greatly
abate them without forcing IRBs to forbid prisoner enrollment in
research studies. Foregoing such blanket exclusion proves extremely
significant as the prison population includes large numbers of AIDS
sufferers. Depriving them of the opportunity to participate in
HIV-related protocols would deny them any chance to receive
treatment, demonstrating that the sole equitable approach with
respect to experimentation in vulnerable populations may be to
permit participation.

The Cognitively Impaired

Protecting the "decisionally impaired" presents a
persistent definitional dilemma. Every individual may be labeled
decisionally impaired at some moment due to causes such as disease,
immaturity, traumatic life events, or side effects of medication.
The term "mentally disabled" remains undefined in federal
regulations, and it seemingly includes a vast array of conditions.
For decisionally impaired persons, reduced decision-making
abilities resulting from illness involving cognitive impairment
and/or the captivity of institutionalization may create
vulnerability. Similar concerns exist in elderly patients suffering
from dementia, depression, and other psychoses frequently seen in
life's advanced stages. Research on those manifesting such problems
poses ethical complications, for psychiatric illness as well as
dementing disorders impact or eradicate a subject's capacity to
furnish valid informed consent. The precise relationship between
possessing sound mind and ability to issue voluntary, informed
consent plagues psychiatrists, judges, and attorneys,[126] as does the concomitant problem of safeguarding
these vulnerable individuals while improving and making treatments
for ravaging illnesses available.

Federal regulations, however, furnish no guidance
on identifying or evaluating decisional capacity for purposes of
participation in experimental protocols. Determination that a
potential subject proves unable to consent to participation means
that such consent must come from a surrogate or proxy, yet
regulations offer scant guidance on this issue. Due to the absence
of regulatory guidance as well as governmental resolve to address
ethical issues pertaining to cognitively impaired research
subjects, numerous organizations have promulgated and adopted
research guidelines in the area. These guidelines put forth several
sliding scales of permissibility and safeguards premised on
categorization of protocols in terms of degree of risk as well as
potential for direct, tangible benefit to the individual
subject.[127] Lack of specific federal direction on research
with decisionally impaired individuals has additionally meant that
non-federally funded protocols have evolved in fifty different
directions: state regulation in this area can be described only as
"a crazy quilt...with most [states] having no rules that clearly
apply to this group while some are quite restrictive."[128]

The decision in T.D. v. N.Y.S. Office of Mental
Health ,[129] for example, bans all state-sponsored research
involving mental patients implicating greater than minimal risk and
denying subjects potential benefits. This result foreclosed
significant research on mental illness, namely department of
psychiatry studies at Cornell, an institution possessing a vast
portfolio of foundation-funded experiments. Clinical studies with
decisionally impaired individuals must continue; performing it
without undercutting the very humanity it aspires to promote will
always demand a delicate balance.[130] If excessive protections are imposed on research
participation of the cognitively impaired individual, they will
disproportionately single him out and aggravate already existing
stigmas. They will additionally deny the cognitively impaired
individuals the equity and fairness afforded to other groups. Among
subclasses of potential participants often regarded as vulnerable
and necessitating stringent protection, the decisionally impaired
are unique in that no federal regulations addressing them exist.
Guidelines, however, are badly needed so researchers can more
easily balance goals of advancing knowledge with safeguarding the
welfare of human subjects.

The complications psychiatric patients present in
securing informed consent further evince the need for such
regulations. Federal guidelines mandate disclosure of any
appropriate alternative courses of treatment which might benefit
the subject, presenting fundamental hardships. Not only do a
greater number of therapies with lesser degrees of certainty about
effectiveness exist in psychiatry than in somatic medicine, but
psychiatrists also often display adamant commitment to a particular
mode of therapy.[131] These doctors thus may hesitate to outline
alternative therapy possibilities to patients. Additionally, the
therapy-patient relationship often is more germane to the progress
and outcome of psychiatric treatment than is the physician-patient
relationship to healing.[132] The trust and confidence a psychiatric patient
places in his doctor proves a crucial component of the therapeutic
relationship, especially where the patient's capacity to verbalize
his thoughts is a significant part of the treatment. It is thus
plausible for psychiatrists to reason that discussion of
alternative modes of therapy might dilute the esteem a patient
holds in his therapist, thereby interfering with the therapeutic
process.[133]

An additional obstacle to securing truly informed
consent from psychiatric patients is the subject's ability to grant
it. Questions of competence need not be raised for the large
numbers of patients seeking psychotherapy for issues such as
marital discontent, and incompetence may be recognized easily in
cases involving patients unable to communicate, but most
psychiatric cases lie in between these two extremes. As with
prisoners, concern about voluntariness of consent arises with
institutionalized patients. Various inherent characteristics of
psychiatric patients, such as dependency, complicate the question
of free consent to a proposed therapy or protocol. This
complication is exacerbated by the fact that psychiatrists often
possess the capacity to sway patients to consent to nearly
anything.

Dealing with subjects whose decision-making
capacities may be impaired is also a concern for investigators
recruiting geriatric subjects, for this involves conducting
research on individuals suffering from depression, dementia, or
other late life psychoses. Safeguarding the elderly who are
cognitively challenged and confined to hospitals or nursing homes
is only one regulation mandating that a scientist procure "legally
effective informed consent of...the subject's legally authorized
representative."[134] Effective trials and experiments must have older
participants currently afflicted with a medical condition under
scrutiny, yet as with other vulnerable populations, these subjects
lack sufficient capacity to grant ethically valid consent to
participate. Standards and procedures for capacity evaluation
should reflect an appreciation that potential subjects need
individual evaluation.[135] Requiring IRBs to involve independent third
parties to succor and supervise consent negotiations involving the
cognitively impaired elderly would improve the current
situation.

While greater uniformity and specificity is needed
in regulations pertaining to research involving all cognitively
impaired classes, focus upon the knowledge and standardized tools
requisite to measure ability to furnish consent to research
participation also proves necessary. Evaluation to Sign Consent
(ESC) is one test that has been developed to determine capacity to
consent in clinical settings. A five-item questionnaire
scrutinizing a subject's factual understanding of information
pertinent to participation in a specific study, ESC could be
employed to ascertain which patients possess sufficient capacity to
grant ethically and legally valid consent. In the test's first
systematic application to a randomized, clinical drug trial,
sixteen of twenty-four subjects failed the assessment.[136] In contrast to ESC, which is a short and
concrete aid inquiring only about study-specific facts, another
standardized measure known as the MacArthur Competence Assessment
Tool-Clinical Research (MacCAT-CR) involves a twenty-page
questionnaire posing questions related to a hypothetical study.
This long and abstract measure examines the effectiveness of the
standardized assessment tool utilized to evaluate capacity to grant
consent. While it may set an unreasonably high standard for
psychiatric subject participation, the ESC test may not be
sufficiently exacting.[137] These are the only two existing assessments of
capacity-to-give-consent research tools in the testing
phase,[138] yet both possess shortcomings. Further research
pertaining to methods of assessing capacity to consent is thus in
order.

Consent Complications in Modern Science: The
Problem of Gene Therapy

Newer, more severe challenges to informed consent
and vulnerability of subjects come with gene therapy. Genetic
research proves likely to have an incredibly profound influence
upon the twenty-first century, and the Human Genome Project already
has impacted the direction of future research. The Project, which
has seen recent successes in identifying and sequencing all sets of
genes that comprise the human being, is expected to enable the
curing of disease through information contained in genomic mapping.
Investigators' hope that the Project will spur a therapeutic
revolution has resulted in extensive promotion of human gene
transfer research as therapy. The thorny ethical and legal dilemmas
this practice raises, however, escalate with each new
discovery.

Perhaps no event in recent human history has done
more to highlight the results of deficient oversight than Jesse
Gelsinger's demise. Pressured by Congress to explain flaws in gene
therapy oversight, federal health officials conceded that they
could not determine whether experiments had hastened or possibly
caused the deaths of other subjects.[139] Subsequent to an NIH reminder, issued in the
wake of the Gelsinger tragedy, to report all adverse occurrences
related to gene therapy trials, 652 new problems surfaced, ranging
from fevers to partial paralysis and death.[140] While admitting that it failed to report
immediately three deaths to a governmental research agency,
Boston's Beth Israel Medical Center stressed that it did inform FDA
yet received no reply. Researchers at Boston's St. Elizabeth's
Medical Center likewise failed to report the death of a patient
involved in a gene therapy experiment that may have contributed to
the development of cancer in another patient. That latter subject's
condition was also improperly reported. As discussion arose as to
why investigators habitually flout federal guidelines to report
experimental side effects in patients to NIH, one explanation
surfaced: the Recombinant DNA Advisory Committee, its panel
supervising gene therapy, lost authority to approve research
protocols in 1996. As a result, scientists ceased to take the body
seriously. Researchers additionally claim confusion surrounds which
governmental agency should receive adverse reports, with NIH
blaming FDA and FDA blaming NIH.

Recognizing that improvements in reporting are
requisite if the public is not to remain skeptical, FDA and NIH
announced an initiative in March, 2000 with potential to impact
review of gene transfer trials profoundly. FDA will demand that
sponsors of gene transfer trials regularly submit monitoring plans
to it, and the Administration will review the plans, demand
alterations where necessary, and supervise as well as inspect
trials to certify proper monitoring. While these policies represent
a significant response to misgivings over gene therapy trial
oversight, they fail to address a large majority of clinical
trials. Many trials occur outside the gene therapy context, and
patients in them face tremendous risk.[141] Innovative research in genetics additionally
illustrates that traditional solutions to consent have grown
obsolete. With DNA banking, for example, disclosure of information
involving the manner of safeguarding privacy, duration of time for
which tissues will be stored, and whether biological material will
be used for secondary research all need to be addressed if a
subject's assent to participation is to be truly "informed" and
voluntary.

A March, 1996 report of the General Accounting
Office additionally concedes that the line differentiating research
from treatment is frequently nebulous to clinicians.[143] Conducting gene transfer studies in the context
of patient care thus creates considerable confusion, with the
blurring of research and therapy exemplified in the term "gene
therapy." The term both signifies novel insights into the workings
of the human body and connotes routine therapeutic
practice.[144] While the former meaning infuses gene therapy
with appeal, the latter interpretation permits experimental
interventions to be prematurely applied clinically as merely
another therapeutic modality.[145]

Another challenge to informed consent and human
subject protection in the context of gene therapy involves
physicians' financial incentives to perform experimental studies,
which create conflicts of interest. Investigators have become
increasingly involved in post-marketing research, prompting
concerns that patient may receive scanty disclosure and that
doctors possess sufficient motivation to sacrifice the interests of
patient-subjects to their own fiscal ends. Concerns that
biotechnology funds alter informed consent prove substantial: at
University of Pennsylvania, the doctor directing the school's
Institute for Human Gene Therapy at the time of the Gelsinger
incident also founded a biotechnology firm in which he holds stock.
This company provided him with the monetary backing for the
Institute. Many researchers in the gene therapy have significant
financial stakes in the field; the doctor overseeing the
aforementioned St. Elizabeth trials likewise is a founder of a
company leading the trials and a major stockholder in it. Such
involvement leads to doubts that clinical researchers enjoying
equity in companies and who stand to gain from genetic
experimentation can be trusted to report serious adverse effects
occurring during such studies and to safeguard patient welfare.
Harvard Medical School harbors this concern, prohibiting scientists
with nontrivial financial interests in companies to participate in
clinical trials of their products.[146] The St. Elizabeth's case demonstrates what may
occur when such policies are absent: necessary tests were not
performed in certain cases, several patients enrolled might not
have been eligible for the study, and one included patient
unquestionably should have been excluded under the experiment's
rules.

Such flagrant "errors" result from rigorous
competition for patients. Pharmaceutical companies typically need
roughly 4000 subjects to test an experimental drug and pay
physicians up to $2500 per patient recruited.[147] Marketplace ideology now pervades medicine,
placing considerable emphasis on profit. This mentality
subordinates both scientific truth and patent welfare. One observer
of new biotechnology laments that "[t]o do science, you need money,
but to raise money competitively you need to project illusions that
are the antithesis of science."[148]

Academic research itself is highly competitive,
with researchers vying for lab space, grants, and top graduate
students. Rewards for innovative research come in the forms of
tenure, promotion, and opportunities at eminent universities and
research sites. These considerations combine with financial
incentives to foster a "permissive attitude toward use of human
subjects" in which informed consent as well as patient autonomy is
undervalued and the "niceties" of disclosure and consent are
overlooked.[149] Scientists seek breakthroughs since continued
financial support directly depends on demonstrated progress. This
creates incentives to inflate claims regarding the therapeutic hope
new interventions may offer. Despite the significant financial and
reputational motivations of investigators, IRBs as well as
individual subjects regularly possess no knowledge of the ways in
which these factors influence the applicable researcher. While
financing has been the most tangible, significant change in
clinical trials over past decades, it remains unaddressed in
federal regulations. Regulatory reform is needed to prevent
monetary considerations from demoting autonomy and subject safety
as well as from bolstering therapeutic misconceptions.

Proposals for Future Improvement in Informed
Consent and IRBs

Problems of informed consent in gene therapy and in
research generally evince that more care must be taken in divorcing
clinical trials from therapy and that more meaningful conversations
between investigators and potential subjects must take place.
Physician-researchers must regard themselves as scientists only,
not as doctors, for they become "double agents with conflicting
loyalties" by conflating research with therapy and subjects with
patients.[150] Legally sufficient consent may not be morally
valid, however, because morally valid consent seeks true
"con-sent," an agreeing together.[151] A rigorous, clear policy mandating full
disclosure could promote autonomy by creating an awareness in
patients not to trust physicians to restore health, but rather to
rely on an experimental protocol to produce valuable knowledge and
perhaps ameliorate their condition. To secure truly valid consent,
researchers should be required to explain: (1) that subjects are
not only patients, and to the extent to which they are patients,
their therapeutic needs will be subordinated to scientific
concerns; (2) that a research protocol and question guide the
experimental study, and individual interests will be subordinated
to scientific concerns; (3) that clinical research seeks to furnish
doctors with information on which treatments are most hazardous,
beneficial, or ineffective; (4) that clinical research may be in
the subject's immediate best interest, future interest, or may
offer no benefit at all, especially if the patient receives a
placebo; (5) that it is uncertain if the patient's welfare would be
promoted through treatment by a physician rather than a
doctor-investigator; and (6) that the researcher will respect
whatever decision the subject ultimately makes.[152] Additionally, informed consent should be deemed
an ongoing process in which preliminary data the study yields is
furnished to subjects, who are assured of continual receipt of
information when they initially consent to participate. Conversing
forthrightly with patients will afford them a more profound
understanding of the difference between clinical research and
therapy.

Informed consent is fundamentally about language
and communication between subjects and researchers as well as
physicians and patients, yet the process currently does not promote
candor. Attention thus should be given to meaningful communication
rather than to supplying mere facts. Doctors enjoy the best
position to foster discussions since subjects and patients may not
possess enough information even to formulate questions or voice
reservations. The medical profession must come to recognize that
patients desire substantial disclosure on dangers and alternatives
to a particular procedure or study both to decide upon a the most
appropriate course of treatment and to know what to expect. On the
other hand, subjects should no longer be barraged with esoteric
medical information that elucidates little and obfuscates basic,
crucial facts needed to issue informed and voluntary consent.
Researchers thus bear an obligation to translate scientific jargon
into language comprehensible and pertinent to subjects and to purge
informed consent forms of distracting, inconsequential technical
information.[153] Consent forms thus require meaningful
alteration, for they currently provide a better understanding of an
investigator's aims to IRBs rather than to potential subjects. Gene
transfer research consent forms, for example, should plainly
indicate that no expected benefit to the individual subject exists.
As George Annas observes,

[W]e must use language to clarify rather than
obscure what we

do to one another. Minimally, we must correctly
identify and

describe roles and responsibilities in human
experimentation...

[I]t may not be realistic to think we can always
distinguish re-

search from therapy, physicians from scientists, or
subjects from

patients. Nonetheless, it's morally imperative to
use language to

clarify....because ignoring these differences
undermines the

integrity of scientific research, the integrity of
the medical profes-

Candor additionally suggests that federal
regulations must require researchers to reveal any and all fiscal
incentives involved in experimentation to potential subjects as
well as to IRBs. Guidelines might also be amended to condition
federal funding on the premise that no institutional employee may
enjoy a personal financial incentive in research. Additionally,
they might require that any profits from research be deposited in
university research accounts and utilized for the good of persons
similar to the subject or to promote study into the condition
examined in the protocol.[155] Such mandates would extend academic conflict
rules existing at many state and local institutions to research
settings nationally, promoting greater uniformity.

Informed consent could further uplift autonomy
through adoption of a "life plan" approach.[156] Researchers would be required to determine a
subject's "life plan," i.e. mindset, to determine what information
is relevant to consent. This approach necessitates moving beyond
boilerplate descriptions of risks and benefits, reflecting a
recognition that not all subjects share identical hesitations,
hopes, vulnerabilities, and levels of risk aversion. Researchers
would thus have to delve into areas such as a patient's education,
current circumstances, life history, and family backgrounds and
devote special attention in detailing a study to aspects this
particular subject would care to know. In some circumstances,
arrangements must be made for consent to be secured by the same
process through an intermediary not directly linked to the
protocol. Such a provision would mitigate possibility for conflicts
of interest and enhance probabilities that subject preferences
receive considerable weight. Medical social workers might serve as
intermediaries and could work with investigators to ascertain the
nature of the research before translating this information into
terms comprehensible to the subject. The intermediary or
investigator must additionally take care to conduct conversations
and secure consent in an uncoercive environment; a pleasant and
familiar setting eases a subject's ability to act freely. The "life
plan" approach thus would respect free choice by discouraging
disclosure shaped by paternalism as well as by heeding a patient's
value judgments, however much a physician disagrees with them.

For trials posing greater than minimal risks to
subjects, mandating use of a subject advocate or surrogate system
involving use of individuals attuned to the needs and concerns of a
subject would also improve informed consent.[157] Jesse Gelsinger's father, a handyman, indeed
stated that "[he] would have liked to have had somebody there who
was not affiliated with Penn that could have assisted in describing
the whole process of gene therapy."[158] An advocate trained to recognize the
psychological complications that accompany terminal diagnoses
likewise can aid patients in confronting depression and in
digesting the information they receive. Surrogates additionally are
able voice concerns that subjects are unable or reluctant to ask.
Researchers with monetary incentives may prove more likely to offer
full disclosure when they recognize that the consent process is
being meticulously scrutinized on a subject's behalf. Until such a
requirement is in place, however, a subject should be advised to
have friends or relatives accompany him to meetings where
physicians detail risks and alternatives of clinical trial
participation. As FDA Commissioner Henney explains, "[i]f they
don't understand something, it might be that [the subject] didn't
either," for patients are "very vulnerable for information that
might sound too hopeful."[159]

Another serious failing of the law of informed
consent is the refusal to recognize that insufficient disclosure of
information to patient-subjects is a wrong worthy of legal
protection. Federal regulations do not adequately stress the
sanctity of human rights, and courts have failed to label a
researcher's shortcomings in securing informed consent an intrusion
into the subject's right of self-determination meriting remedy. To
safeguard the dignity and autonomy of patients, a cause of action
for nondisclosure, based upon fiduciary and negligence law, should
be developed. Fiduciary principles demand the most exacting levels
of disclosure and performance from a fiduciary, and the law demands
that such an individual who acts in his own interest compensate the
dependent party. Courts may assess damages upon the deviating
fiduciary or award profits the fiduciary earns to the dependent
party. Under this approach, a fiduciary relationship would arise
from the ties between investigator and subject, the former charged
with securing informed consent in a manner that accommodates the
latter's individual values and desires.[160] Upon finding a breach of fiduciary duty, a court
could, inter alia , apply general damages for the breach and
for emotional harm, impose punitive damages upon a scientist for
wanton, willful, or reckless disregard of a subject's autonomy,
demand special damages for proven losses, or apply equitable
remedies such as creating a constructive trust upon pecuniary gain
when researchers fail to disclose monetary incentives.[161]

Another reform which would benefit patients would
be to create a national human investigation board. Large-scale
collaborative research protocols have made the monitoring of
research trials a daunting task, rendering a federal agency with
rule-making and adjudicatory power over affairs pertaining to human
experimentation desirable. Such a body could fashion research
policies, function as a source with which local IRBs could consult
for guidance, and publicize decisions rendered by itself as well as
local IRBs. It additionally would facilitate possibility for
consistency and comprehensiveness of the review process within and
between IRBs, whose decisions are largely matters of judgment
influenced by local considerations.

Boards typically focus on risk-benefit ratios and
consent forms, which often fail to furnish relevant information to
subjects in any comprehensible way, thus rendering these bodies
unlikely to promote meaningful consent. In addition or as an
alternative to a national body, IRBs could be required to monitor
especially risky research, protocols involving vulnerable subjects,
situations where an investigator has a significant conflict of
interest, and trials less likely to attract outside or press
scrutiny.[162] While IRBs have functioned primarily as
paperwork gatekeepers to the initiation of human research rather
than as watchdogs continuously overseeing investigators' ongoing
actions, the Office for Protection from Research Risks reports:

IRBs could additionally promote consent further by
employing waiting periods between an investigator's invitation to a
subject to participate and the signing of the consent form for
entry into a study, thus allowing the patient time to comprehend
and consider participation. They might additionally observe or have
a third party observe the consent process. Such reforms could be
effected if NIH permits additional grant funds to institutions to
furnish necessary resources for IRBs.

Improved monitoring alone proves insufficient,
however, for a more fundamental difficulty- i.e. confusion over
what precise function an IRB is supposed to perform- exists and can
be remedied only by altering the composition of these bodies. IRBs
serve as scientific, technical, institutionally-grounded
peer-review bodies which evaluate risk-benefit ratios and ensure
that investigators work to minimize hazards. Yet, they also are
intended to serve a "representative" function as the conscience of
the broader local community in assessing community approval of the
risk-benefit ratio. These two tasks are irreconcilable given the
current composition of these bodies, for dominance by medical
researchers creates fundamental obstacles to boards' capacities to
review critically the content of information furnished as part of
the informed consent process. Highly trained scientists occupy no
position to determine what a reasonable patient would care to know.
Federal regulations must be altered to permit greater IRB
participation by nonscientists as well as those lacking links to
research institutions. One possibility is a dual committee system,
where one completely professional body would scrutinize only the
scientific aspects of a proposed protocol to ensure minimization of
risk and to consider the significance of information that might be
acquired. A second group comprised of external, community based
members would debate community acceptability of the risk-benefit
calculus.[164]

Another alternative is to require that at least
half of the members of all ethical review bodies be composed of
nonresearchers and nonphysicians, which would highlight the degree
to which a scientist's goals digress from those of ordinary
citizens. In Denmark, for example, guidelines traditionally
mandated that such committees have three lay members as well as
three medical members, reflecting an awareness that lay members can
be overawed when medical personnel dominate a committee.[165] Evincing the Dane conviction that medical ethics
are of concern to society at large, the country's Parliament passed
a bill in 1992 requiring that one lay member more than the number
of professional members always occupy a reviewing body. Observers
report that lay members frequently offer the most valuable
contributions and that they seem better positioned to recognize
inappropriate risk-benefit sacrifices.[166] Public access may additionally render IRBs more
likely to perform effectively and will strengthen public confidence
in the research review process.

Improvement additionally necessitates greater
government enforcement of IRBs. NIH's Office of Protections from
Research Risks (OPRR) and FDA are the two entities within the DHHS
responsible for IRB oversight. OPRR primarily performs this
responsibility by demanding renewed assurances from IRBs, i.e.
documents declaring the institution's commitment to respect human
subject participation guidelines as well as policies and procedures
for meeting regulations. OPRR additionally conducts a limited
number of IRB inspections, but reviews are largely in response to
complaints or concerns about compliance. FDA also inspects clinical
investigators, IRBs, and sponsors. Since June, 1998, the
enforcement of federal human subject protection requirements has
escalated, with FDA and OPRR intensifying their on-site presence at
research institutions. The latter's activities have proven
particularly effective in demanding the research community's
attention to IRB oversight as well as to human subject protections,
and influential medical journals have devoted attention to OPRR's
enforcement actions.[167] DHHS agencies, however, seldom move beyond the
aforementioned oversight mechanisms: FDA inspections, for example,
remain narrow and focused on compliance. FDA should adopt a more
results-oriented approach to its inspections, devoting greater
attention to the manner in which individuals are invited to
participate in research as well as to how and the degree to which
IRBs are rendering ongoing assessments of risk-benefit
trade-offs.[168]

IRBs alone, however, cannot perfect the research
review process: their current overextension demands reform
providing for greater education of investigators rather than for
mere fortification of these bodies as well as the oversight
process. Sponsors, researchers, and their institutions are
collectively responsible for creating and sustaining a setting
which elevates the rights and welfare of subjects. This demands a
steady educational effort. The IRB system largely relies upon
researchers' dedication to respecting human subject protections,
yet it offers little educational outreach or continuing guidance to
investigators to help them become informed and sensitized about
safeguards.[169] Given the explosion in IRB numbers as well as
the intricacy of issues they now confront, novel educational
efforts are necessary. NIH may promote such efforts by increasing
the educational staff and budget of OPRR, part of whose mission is
to clarify ethical issues which human research presents. It may
additionally offer competitive grants to fund studies on innovative
educational strategies tailored to IRBs and researchers.[170]

Promulgation of new international research rules
additionally is desirable. The United Nations should formulate a
Covenant on Human Experimentation premised upon the Nuremberg Code,
covering all non-therapeutic research as well as therapeutic
research on competent individuals.[171] Provisions pertaining to children, the
cognitively impaired, and the terminally ill should also be
included. An international tribunal on human experimentation also
needs to be established. Without a body possessing authority to
judge and chastise investigators who violate international norms,
we cannot alter a status quo where international norms of human
research are subordinated to the domain of ethics and are
disregarded in that domain. A tribunal enables international ethics
to bear the force of law.

Improving patients' rights in clinical trials and
experiments proves crucial since our quest for the medical "Holy
Grail" has repeatedly had destructive consequences for individual
subjects. As Bertolt Brecht warns in a play authored shortly after
Hiroshima,

Human trials prove indispensable in the acquisition
of knowledge to relieve human suffering, yet investigators'
invocations of their moral right to perform experiments on
individual human beings too often ignore how the invitation to
participate can be offered so as to respect one's right to personal
autonomy and integrity. Too often we have merely given lip service
to subjects' rights to full information, yet it remains
indefensible to manipulate some human beings for the ends of
others. Regulations must be altered and experimental procedures
formally reformed to clarify the distinction between research and
therapy as well as the attendant confusion of subjects and
patients, to differentiate between the goals of medicine and
research, to change the impact of the ideology of medical
professionalism upon the conduct of human experimentation, and to
delineate clearly the principles governing participation of
different groups in research. Law is the appropriate tool to
improve human subject protection, for its represents a socializing
force instructive of community moral and social norms. It
additionally serves a declaratory role in offering authoritative
statements of morality and exerts a socializing influence by
furnishing a framework for moral education.[173] Over time, then, the law can shape the behavior
and thinking of scientific investigators. Promulgation of varying
guidelines for different research populations promotes formal
recognition that a single monolithic standard governing human
subject protection disregards human autonomy and ignores society's
multifarious needs.

Reforms in codes, regulations, and procedures
alone, however, will not be sufficient to elucidate societal goals
for research as well as the conduct of medicine or to describe the
meaning of progress.[174] Resolution of these fundamental issues
necessitates concession of both society and investigators that
immortality is not a reasonable aim for medicine or mankind as well
as recognition that quality of life may be more important to some
human beings than its quantity. Individual dignity cannot be
abandoned in the quest for progress. If informed consent is to
reach its full potential to safeguard the rights of human research
subjects, mankind must consider the following challenge posed by
philosopher Hans Jonas:

[9] It may be plausibly argued that public debate in the
United States did not immediately ensue. Not until Henry Beecher's
article did the government begin to confront ethical issues
pertaining to human subject experimentation. For example, the
Supreme Court rejected the opportunity to adopt Nuremberg Code
principles. See Karine Morin, The Standard of Disclosure
in Human Subject Experimentation , 19 J. LEGAL MED. 157, 157
n.1 (1998).

[14]See Jonathan D. Moreno, Regulation of
Research on the Decisionally Impaired: History and Gaps in the
Current Regulatory System , 1 J. HEALTH CARE L. & POL'Y 1,
9 (1998).

[15] Adding to the egregiousness of the study was the
denial of treatment after the invention of penicillin in 1947 and
the dissuasion of the subjects from seeking services where they
might receive treatment with penicillin for other conditions.
See Holmes-Farley and Grodin, supra note 11, at
187.

[22] It should be noted that numerous additional
controls operate to regulate the conduct of research apart from
those which directly involve interaction with human subjects.
Individual institutional policies, for example, often demand
disclosure or prohibition of financial conflicts of interest, and
other federal regulations require suspension of eligibility for
financial assistance of organizations and individuals who commit
financial abuse. See Goldner, supra note 16, at
89.

[44] For example, heart transplantation and surgical
palliation of hypoplastic left heart syndrome is a "last resort"
measure to treat a defect that is inevitably fatal, usually within
weeks. One doctor expresses concern that if she reveals the
procedure's availability to parents, they will feel pressured to
pursue it and experience guilt if they do not try "everything
possible" to save their child's life. See King and
Henderson, supra note 4, at 1036.

[72] Another difficulty surrounding consent which AIDS
and AZT highlight is the practice of administering placebos to a
control group. One cannot help but question the ethical propriety
of withholding the only potential treatment from terminally ill
patients to acquire accurate data for future generations. In 1997,
US-sponsored HIV research involving AZT in developing countries
attracted considerable criticism since clinical trials involved
placebo-controlled testing among pregnant HIV+ subjects. It is
difficult to accept that patients will consent to participation in
such studies if truly informed consent about risks and
alternatives- namely that placebos offer no protection- occurs.
Justifications for withholding information on placebos, including
that the investigator does not know with certainty that placebo is
inferior as well as that a patient will grow distressed if she
learns she is being given a "less desirable" treatment, clearly
undermine goals of promoting autonomy and informed choice.

[82] These exclusionary policies prove misguided since
they fail to address the root of the problem. The thalidomide
crisis, for example, may have been averted through controlled,
pre-marketing research. See id . at 208.

[86] Doctors may additionally incur liability for
delivering treatments without informed consent since the
possibilities for harm caused by drugs are unknown and patients do
not anticipate being given untested medication or participating in
de facto experiments when they visit their doctor. By excluding
women from clinical trials, liability is not eliminated but instead
passed from researchers to physicians, who become susceptible to
malpractice suits for administering drugs with scarce knowledge of
potential ramifications.

[157] To ensure free choice as well as the viability
of this suggestion, subjects must be able to decline to use a
subject advocate, and advocates should be employed only to the
extent necessary to guarantee adequacy of informed consent.
See Addicott, supra note 64, at 519-20.